AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1

Journal article

Doshi, Heena, Spengler, Katrin, Godbole, Amod, Gee, Yi Sing, Baell, Jonathan B., Oakhill, Jonathan, Henke, Andreas and Heller, Regine. (2023). AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1. Microbiology Spectrum. 11(5), pp. 1-22. https://doi.org/10.1128/spectrum.00417-23
AuthorsDoshi, Heena, Spengler, Katrin, Godbole, Amod, Gee, Yi Sing, Baell, Jonathan B., Oakhill, Jonathan, Henke, Andreas and Heller, Regine
Abstract

Herpes simplex virus type 1 (HSV-1) is a widespread contagious pathogen, mostly causing mild symptoms on the mucosal entry side. However, systemic distribution, in particular upon reactivation of the virus in immunocompromised patients, may trigger an innate immune response and induce damage of organs. In these conditions, HSV-1 may infect vascular endothelial cells, but little is known about the regulation of HSV-1 replication and possible defense mechanisms in these cells. The current study addresses the question of whether the host cell protein AMP-activated protein kinase (AMPK), an important metabolic sensor, can control HSV-1 replication in endothelial cells. We show that downregulation of the catalytic subunits AMPKα1 and/or AMPKα2 increased HSV-1 replication as monitored by TCID50 titrations, while a potent AMPK agonist, MK-8722, strongly inhibited it. MK-8722 induced a persistent phosphorylation of the AMPK downstream targets acetyl-CoA carboxylase (ACC) and the rapamycin-sensitive adaptor protein of mTOR (Raptor) and, related to this, impairment of ACC1-mediated lipid synthesis and the mechanistic target of the rapamycin complex-1 (mTORC1) pathway. Since blockade of mTOR by Torin-2 as well as downregulation of ACC1 by siRNA also decreased HSV-1 replication, MK-8722 is likely to exert its anti-viral effect via mTORC1 and ACC1 inhibition. Importantly, MK-8722 was able to reduce virus replication even when added after HSV-1. Together, our data highlight the importance of endothelial cells as host cells for HSV-1 replication upon systemic infection and identify AMPK, a metabolic host cell protein, as a potential target for antiviral strategies against HSV-1 infection and its severe consequences.

KeywordsHSV-1; AMPK; MK-8722; ACC; mTORC; endothelial cells; antiviral strategies
Year01 Jan 2023
JournalMicrobiology Spectrum
Journal citation11 (5), pp. 1-22
PublisherAmerican Society for Microbiology
ISSN2165-0497
Digital Object Identifier (DOI)https://doi.org/10.1128/spectrum.00417-23
Web address (URL)https://journals.asm.org/doi/10.1128/spectrum.00417-23
Open accessPublished as ‘gold’ (paid) open access
Research or scholarlyResearch
Page range1-22
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Open
Output statusPublished
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PrintSep 2023
Publication process dates
AcceptedJul 2023
Deposited12 Mar 2024
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Copyright © 2023 Doshi et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
https://creativecommons.org/licenses/by/4.0/

Place of publicationUnited States
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